Melatonin, represented by the two-dimensional structure I below, ##STR2## is named systematically as N-[2-(5-methoxy-3-indolyl)ethyl]acetamide. A trivial name for the same compound is N-acetyl-5-methoxytryptamine. Melatonin is a pineal gland hormone. Chu, Wortman and Axelrod, Endocrinology, 75, 238 (1964) inhibited both the estrous phase of the estrous cycle and ovulation in rats and mice with melatonin--see also Ying and Greep, Endocrinology, 92, 333 (1973).
Some substituted melatonins have been prepared. For example, Frohm et al, Life Sci., 27, 2043 (1980) prepared N-acetyl 5,6-dimethoxytryptamine and also longer alkyl chain N-acyl derivatives. Flaugh and coworkers, J. Med. Chem., 22, 63 (1979) prepared 6-chloro and 6-fluoromelatonin. These compounds showed increased ovulation blocking activity. .alpha.-methyl-6-chloromelatonin was also prepared, but .alpha.-methyl substitution was found to have no significant effect on ovulation-blocking activity. 6-chloromelatonin and congeners are claimed in Flaugh and Clemens, U.S. Pat. No. 4,087,444.
7-Chloromelatonin, C.A., 63, 18192a (1965) was prepared as an intermediate in the synthesis of 10-methoxy-12-chloroisodiserpidic acid via a Fischer indole synthesis from the 2-chloro-4-methoxyphenylhydrazone of 2,3-piperidinedione to yield 6-methoxy-7-chloro-1,2,3,4-tetrahydro-.beta.-carboline. Treatment of this carboline with ethanolic potassium hydroxide gave 5-methoxy-7-chlorotryptamine-2-carboxylic acid. Decarboxylation followed by acetylation of the decarboxylated material yielded 7-chloromelatonin.
6,7-Dihalomelatonins and in particular, 6,7-dichloromelatonin, are not known. It is an object of this invention to provide such compounds via a novel synthetic method useful also in preparing 6 or 7-halomelatonins.